Catheter lock solution comprising sodium citrate and benzyl alcohol

ABSTRACT

This disclosure generally relates to catheters, methods of enhancing the patency of an intravascular catheter and compositions, methods, devices and kits relating to the infusion of a catheter lock solution into an indwelling catheter. Disclosed compositions, methods, devices and kits aid in diminishing the effects of microbial infection in catheters and occlusion of the catheters. A representative lock solution includes about 10% sodium citrate and about 1.5% benzyl alcohol. The solution has a density approximating the density of blood for retention of the solution in a catheter during the lock period.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Patent App. No.62/590,536 filed Nov. 25, 2017, the contents of which are herebyincorporated by reference herein in their entirety.

FIELD OF THE INVENTION

The present disclosure relates to catheters and methods of enhancing thepatency of intravascular catheters. More specifically but notexclusively, this disclosure relates to infusing a 10% sodium citratewith benzyl alcohol lock solution into an indwelling intravascularcatheter and to methods of inhibiting infection in an animal having anindwelling intravascular catheter.

BACKGROUND

Approximately 360,000 U.S. patients with end-stage renal disease (ESRD)receive maintenance hemodialysis, approximately 25%—90,000patients—through catheters. Loss of catheter patency because ofthrombosis, an ever-present threat, is a common reason a catheter needsto be replaced, and hemodialysis catheters are routinely locked with ananticoagulant solution between dialysis sessions, in most North Americacenters, unfractionated heparin. This practice has been associated withan increased risk of hemorrhage and heparin-induced thrombocytopenia.Despite prophylactic use of a heparin-containing lock solution,declining catheter blood flow from intraluminal thrombus underlies thenecessity to instill a thrombolytic such as tissue plasminogen activatorinto the catheter lumens of more than half of hemodialysis catheters inan effort to restore patency.

The greatest threat to the safety of patients dialyzed through cathetersis catheter-related bloodstream infection (CRBSI); rates in recentprospective studies have ranged from 2 to 5 cases per 1000catheter-days. CRBSI also commonly results in loss of the catheter andis associated with significant morbidity, including septic shock and agreatly increased risk of infective endocarditis, and has anattributable mortality of at least 10%. It has been estimated thatbetween 67,500 and 150,000 U.S. dialysis patients acquire a CRBSI eachyear.

In order for microorganisms to cause CRBSI they must first gain accessto the extraluminal or intraluminal surface of the implanted devicewhere they can adhere and become incorporated into a biofilm that allowssustained colonization and, ultimately, hematogenous dissemination. MostCRBSIs originating from permanent cuffed and tunneled central venouscatheters are caused by intraluminal contaminants. A promising approachto prevention of these infections involves instilling—locking—ananti-infective solution into each catheter lumen when not in use toprevent colonization of the intraluminal surface by planktonic-phasemicroorganisms which have gained access and can form a biofilm on theinner wall of the catheter. A wide variety of anti-infective locksolutions have been studied in randomized trials for prevention of CRBSIwith hemodialysis catheters, and most have shown benefit.

Measures for prevention of CRBSI are most likely to be effective if theyare based on a sound understanding of pathogenesis. With short-termnon-cuffed central venous catheters, microorganisms from the patient'sskin about the insertion site which gain access extraluminally orintraluminally are the source of most catheter-related BSIs. Over thepast decade, U.S. hospitals which have taken a highly organized, systemsapproach, which starts with formal training of personnel who insert andcare for central venous catheters and focuses on limiting femoral veininsertions, use of maximal sterile barriers during catheter insertion,disinfecting insertion sites with tincture of chlorhexidine rather thaniodine-based antiseptics, and promptly removing unneeded catheters, havereported striking reductions in the incidence of central venouscatheter-associated BSI within their intensive care units.

With long-term intravascular devices, including permanent cuffed andtunneled central venous catheters, most CRBSIs derive frommicroorganisms that have gained access to the catheter lumen during useof the device. Basic infection control with hemodialysis cathetersrelies upon the use of maximal sterile barriers at insertion and sterilebarriers and chlorhexidine disinfection when accessing the catheter andcarrying out insertion site care, and a high level of consistency hasbeen associated with a lower risk of CRBSI. Nonetheless, realizing thatthe rates of CRBSI reported in recent trials with permanent hemodialysiscatheters have ranged between 2 and 5 per 1000 catheter-days, there isclearly a role for innovative technologies designed to preventmicroorganisms from colonizing the implanted catheter, negating theimpact of poor aseptic technique or unique patient vulnerability.

The antimicrobial catheter lock is an innovative technique of localprophylaxis in which an anti-infective solution is instilled into thecatheter lumen and allowed to dwell for a prescribed period of time, inthe case of hemodialysis catheters for the 2 to 3 day interval betweendialysis sessions. In maintenance hemodialysis, a variety ofanti-infective solutions have been evaluated in comparativetrials—nearly all of which have been in single centers—including theantibiotics vancomycin, gentamicin, cefotaxime and minocycline, eachwith heparin; taurolidine in combination with citrate;ethylenediaminetetraacetic acid (EDTA), alone or in combination withantibiotics; citrate, alone or in combination with an antibiotic ortaurolidine; and ethanol with heparin. Four recent meta-analyses of theindividual prospective randomized controlled trials published since 1997each found a significant reduction in the overall incidence of CRBSI,with a pooled risk reduction in the range of 0.30 to 0.40. None of theindividual trials found any evidence that the use of anti-infective locksolutions promoted antimicrobial resistance. However, eight months aftera large outpatient hemodialysis program adopted routinegentamicin-heparin lock prophylaxis for 1488 patients dialyzed in eightunits, CRBSIs caused by gram-positive organisms resistant to gentamicin,primarily coagulase-negative staphylococci and enterococci, wereencountered; 34 infections were ultimately identified over three years,prompting discontinuation of gentamicin lock prophylaxis. A hemodialysisprogram in New Zealand recently also reported a modest increase ingentamicin resistance of coagulase-negative staphylococci recovered fromCRBSIs after adopting gentamicin locks. It seems clear thatanti-infective lock solutions with activity against multi-resistantgram-positive and gram-negative bacteria as well as fungi, but whichwill not promote antimicrobial resistance, are needed. However,antiseptic compounds such as taurolidine and high concentrations ofalcohol kill bacteria by denaturing proteins and carbohydrates. Thismeans that they also denature the clotting factors (which are protein)and tend to increase coagulation within catheters and resultantobstruction. High concentrations of alcohol also tend to weaken ordamage the plastic materials used for construction of most centralvenous catheters.

Prevention of catheter loss from intraluminal thrombosis poses a majorchallenge to stable vascular access in hemodialysis. Dialysis centersroutinely lock both lumens of the catheter with an anticoagulantsolution at the conclusion of each dialysis session. Whereas citrate iscommonly employed in Europe, heparin is used most widely in U.S.centers, in concentrations ranging from 1,000 to 10,000 units/mL. Evenwhen the volume of lock solution is matched to the volume of the lumen,a substantial amount leaks into the systemic circulation, and prolongedpartial thromboplastin times can persist for up to 4 hours afterdialysis.

The use of heparin in the hemodialysis catheter lock solution has beenlinked to a significantly increased risk of bleeding, especially inchildren. Heparin-induced thrombocytopenia, which in its full-blown Type2 form is associated with devastating thromboembolic complications,occurs in 0.5 to 4% of patients on maintenance hemodialysis when heparinis used in the lock solution. Moreover, heparin antibodies, which arenow detectable in many chronic hemodialysis patients, have been linkedto increased cardiovascular mortality. In 2008 heparin manufactured inChina was implicated in thousands of cases of illness and hundreds ofdeaths around the world because of toxic concentrations of oversulfatedchondroitin sulfate in the final product. Finally, there is evidencethat heparin promotes biofilm formation. It seems clear thatantithrombotic strategies other than heparin are needed to preserve thepatency of hemodialysis catheters.

Moderate concentrations of citrate in a lock solution, in the range 4 to10%, have been shown to provide protection against patency failure ofpermanent hemodialysis catheters comparable to heparin in comparativetrials; however, these concentrations have weak antibacterial activityand do not offer protection against infection. Much higherconcentrations of citrate, in the range of 10-47%, have antibacterialactivity and are further active against bacterial biofilms, and havebeen shown in randomized clinical trials to reduce the risk of CRBSI.However, these concentrations cause a rapid egress of lock solution fromthe catheter due to high density of the citrate, and theseconcentrations of citrate have been linked to fatal cardiac arrhythmiasand are unlikely to gain approval from the Food and Drug Administration.

Significant resources are currently being invested in a search foralternative ways to lock catheters and, in particular, to developformulations that have effective antimicrobial and anticoagulationproperties. There is a continuing need for advancements in the field ofcatheter lock solutions. The present invention addresses this need.

SUMMARY

Disclosed herein are compositions, methods, devices and kits relating tothe infusion of a catheter lock solution into an indwelling catheter.

In one aspect of the disclosure, a catheter lock solution is used toprevent clotting of central venous catheters and to kill bacteriacontaminating the interior lumen of the catheters comprising about 10%concentration of sodium citrate dihydrate, and 0.5 to 1.5% benzylalcohol.

In a further aspect of the disclosure, the catheter lock solution isadjusted to a pH range of about 6.0 to about 6.5 by addition of citricacid or other form of acid.

In additional aspects of the disclosure, a method to prevent clotting ofcentral venous catheters and to kill bacteria contaminating the interiorlumen of the catheters using a catheter lock solution comprising a 10%concentration of sodium citrate dihydrate, and 0.5 to 1.5% benzylalcohol.

In one form, the disclosure provides aqueous antimicrobial solutioncomprising about 9 to about 11% by weight citrate and about 1.0 to about2.0 percent by weight benzyl alcohol dispersed or dissolved therein. Inone embodiment, the aqueous antimicrobial solution is an aqueouscatheter lock solution. The citrate and the benzyl alcohol preferablyhave concentrations effective to eliminate infection and to reduce thelikelihood of subsequent infections. The citrate can advantageously beprovided in the form of trisodium citrate dihydrate (referred to hereinas “citrate”) or other citrate salt. The relative density of thesolution is selected in certain embodiments to be similar to therelative density of a patient's blood, and to thereby optimize thelength of time that the solution remains in a catheter. The solution inother embodiments also includes a viscosifying agent and/or additionalpharmaceutically acceptable materials.

In another form, the present disclosure provides a method for treatingpatients having an indwelling intravascular catheter. In one embodiment,the method comprises selecting a patient having an indwelling catheterdefining a lumen therethrough; and infusing an aqueous catheter locksolution into the lumen, the solution comprising citrate and benzylalcohol dispersed or dissolved therein according to any embodimentdescribed in this disclosure. The disclosure is particularly useful intreating a patient having an infection or a substantial risk ofinfection related to the presence of the catheter.

In yet another form of the disclosure, there is provided an infusiondevice for infusing a lock solution into a lumen of a catheter. Thedevice includes a syringe and a pharmaceutically acceptable locksolution contained within the syringe. The lock solution includescitrate and benzyl alcohol dispersed or dissolved therein according toany embodiment described in this disclosure. In a preferred embodiment,the syringe containing the lock solution is sterilized.

The disclosure also provides a method of treating animals having asurgically implanted catheter. The method includes infusing into thecatheter a pharmaceutically acceptable lock solution comprising abactericidal component that consists essentially of citrate and benzylalcohol according to any embodiment described in this disclosure. In apreferred embodiment, the bactericidal component does not include anantibiotic.

In another form, the present disclosure provides a kit for locking apatient's catheter. The kit includes a container having therein acatheter lock solution comprising citrate and benzyl alcohol dispersedor dissolved therein according to any embodiment described in thisdisclosure; and instructions, recorded in a medium, for infusing thesolution into a lumen of an indwelling catheter.

While the actual nature of the disclosure covered herein can only bedetermined with reference to the claims appended hereto, certain formsand features, which are characteristic of the preferred embodimentsdisclosed herein, are described briefly follows.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned and other features of this disclosure, and themanner of attaining them, will become more apparent and the disclosureitself will be better understood by reference to the followingdescription of embodiments of the disclosure taken in conjunction withthe accompanying drawings, wherein:

FIG. 1 is a perspective view of one embodiment of a catheter and syringefor infusing a lock solution into a catheter for use with the presentdisclosure.

FIG. 2 is a MIC of LS A (Lock Buffer A, sodium citrate) against sixpathogens (A) Escherichia coli O157:H7 EDL933, (B) Staphylococcus aureusATCC25923 (non-MRSA), (C) Staphylococcus aureus ATCC43300 (MRSA), (D)Streptococcus mutans ATCC 25175, (E) Pseudomonas aeruginosa ATCC10145,(F) Klebsiella pneumoniae ATCC33495. + Control, bacterial cultureswithout treatment, and − Control is media only.

FIG. 3 is a MIC of LS B (Lock Buffer B, sodium citrate with benzylalcohol) against six pathogens (A) Escherichia coli O157:H7 EDL933, (B)Staphylococcus aureus ATCC25923 (non-MRSA), (C) Staphylococcus aureusATCC43300 (MRSA), (D) Streptococcus mutans ATCC 25175, (E) Pseudomonasaeruginosa ATCC10145, (F) Klebsiella pneumoniae ATCC33495. + Control,bacterial cultures without treatment, and − Control is media only.

FIG. 4 is a graph of the susceptibility of S. aureus biofilms to varioustested solutions (heparins, C/MB/P) following 48 h treatment understatic conditions. Log reduction for flow cell-grown biofilms (whitebars) and for flow cell-grown biofilms plus S. aureus cells present inthe bulk liquid (grey bars) was determined by viability counts.**P<0.01. Error bars indicate 1 SD.

FIG. 5 is a chart summarizing the MIC of C/MB/P versus several pathogens(ATCC and hospital isolates) expressed as % of the originalconcentration of C/MB/P.

Corresponding reference characters indicate corresponding partsthroughout the several views. Although the drawings representembodiments of the present disclosure, the drawings are not necessarilyto scale and certain features may be exaggerated in order to betterillustrate and explain the present disclosure.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to the embodiments disclosedherein and specific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, any alterations and further modificationsin the illustrated embodiments, and any further applications of theprinciples of the invention as illustrated therein as would normallyoccur to one skilled in the art to which the invention relates arecontemplated herein. Moreover, it should be understood that when certainvalues and ranges are recited herein in connection with variousembodiments of the present teachings, all values and ranges which fallbetween such listed values and ranges are intended to be encompassed bythe present teaching unless explicitly stated otherwise. Finally,although specific methods and materials are described herein withrespect to certain exemplary aspects of the present teachings, it shouldbe understood and appreciated that other methods and materials similaror equivalent to those described herein can be used in the practice ortesting of the present application without straying from the invention'sintended scope.

The embodiments disclosed below are not intended to be exhaustive orlimit the disclosure to the precise forms disclosed in the followingdetailed description. Rather, the embodiments are chosen and describedso that others skilled in the art may utilize their teachings.

In one aspect, the present disclosure provides a catheter lock solutionoperable to provide anticoagulant and antibacterial properties to animplanted catheter as the lock solution resides in the catheter betweenuses. As used herein, the term “lock solution” refers to a solution thatis injected or otherwise infused into a lumen of a catheter with theintention of allowing at least a portion of a lock solution to remain inthe lumen until it is desired or required to access that particularlumen again, typically for additional treatment, i.e., infusion orwithdrawal of fluid. It is desired that at least a portion of the locksolution remain in the lumen for a desired amount of time lasting fromabout 1 hour to 3 or 4 days or longer. However, frequently the locksolution is changed on a daily basis during regular care and sterilemaintenance of the indwelling catheter. Use of a lock solution inaccordance with the present disclosure provides particular advantagesfor patients with catheters by inhibiting catheter-related infectionsand by preventing catheter occlusion.

A catheter used in connection with the present disclosure typically caneither be an acute (temporary) or chronic (long-term) cathetersurgically implanted in an animal. The catheter usually is inserted intoa vein or artery, but can be inserted into any other liquid-filledcavity of the body. The catheter is typically used in varying intervalsto administer fluids, nutrients, and medications into the body. Thecatheter also can be used to withdraw body fluids, such as blood forhemodialysis treatment. When not in use, the catheter remains in itsposition, commonly an intravascular position, until a subsequenttreatment is performed.

The catheters that may be used in accordance with this disclosureinclude known and commonly used catheters and are readily available froma variety of commercial sources. The catheters may vary in configurationand size. One type of catheter commonly used in accordance with thisdisclosure is a tunneled catheter that includes a cuff for ingrowth oftissue to anchor the catheter. Catheters containing totally subcutaneousports are also useful in the present disclosure. The catheters aremanufactured to function for several months with proper intervention.However, in actual practice prior to the present disclosure, thecatheters have exhibited limited longevity because of occlusion and/orinfection. The catheters frequently must be removed and/or replaced uponthe occurrence of occlusion and/or infection.

FIG. 1 depicts one example of a catheter 10 for use with thisdisclosure. Catheter 10 is a dual lumen catheter and includes an outersheath 12 having a cuff 38 and first and second lumens 14 and 16,respectively. Lumens 14 and 16 extend from distal tip 18 through sheath12 and exit from sheath 12 at connection 36. Each of lumens 14 and 16include releasable clamps 20 and 22, respectively. Each of lumens 14 and16 terminate in a threaded end 24 and 26, which can be threadedlyattached to protective end caps 28 and 30, respectively. Fluidsincluding a lock solution can be infused or withdrawn from each lumen 14and 16 by making a Luer connection between a syringe 34 and the ends 24and 26 of catheter 10. Alternatively, fluids can be infused or withdrawnfrom each lumen by inserting a needle (not shown) through protective endcaps 28 and/or 30 after protective end caps 28 and/or 30 have beensterilized by cleaning successively, for example with Betadine andalcohol. As yet another alternative, one or both protective end caps 28and 30 can be removed and threaded ends 24 and 26 can be threadedlyattached via a connector (not shown) to lines for infusion or withdrawalof fluids (not shown). Once a desired treatment session has beencompleted, the lumens are typically flushed with normal saline, afterwhich a lock solution is injected into each lumen and fresh, sterileprotective end caps are placed on the ends 24 and 26 of the catheter.All procedures are performed using standard sterile techniques wellknown to these skilled in the art. The catheters for use with thisdisclosure can be prepared from a variety of materials, including, forexample, silicon, polyurethane, polyurethane-polycarbonate copolymer,polyvinyl, silicone, or silastic elastomer.

In one form, the present disclosure provides a catheter lock solutionincluding citrate and benzyl alcohol dispersed or dissolved therein. Thecitrate in one preferred embodiment is provided in the form of a citratesalt such as, for example, trisodium citrate dihydrate.

In an exemplary citrate/benzyl alcohol catheter lock solution, the totalconcentration of the benzyl alcohol is from about 0.5 to about 2.0percent by weight. In another embodiment, the total concentration of thebenzyl alcohol is from about 0.5 to about 1.7 percent by weight, and inyet another embodiment, the total concentration of the benzyl alcohol isfrom about 1.0 to about 1.7 percent by weight.

Although it is not intended that the present disclosure be limited byany theory whereby it achieves its advantageous results, it is believedthat the citrate prevents coagulation by chelating the calcium in theadjacent blood. Decreasing the citrate concentration decreases theeffect of calcium to catalyze numerous reactions that form blood clots.Citrate as an anticoagulant catheter lock is preferably present at aconcentration at least as high as necessary to significantly decreasethe ionized calcium concentration in blood, even when the lock solutionis diluted by blood at the tip of a catheter. In one preferredembodiment, sodium citrate is present in a lock solution at aconcentration of from about 5 to about 11 percent by weight. In anotherembodiment, citrate is present at a concentration of from about 6 toabout 10.5 percent by weight.

The above concentrations are presented as “percent” of mostly trisodiumcitrate dihydrate in water. When various combinations of salts ofcitrate are combined, such as trisodium citrate with citric acid, forexample to obtain a certain pH, it is more accurate and helpful toexpress the concentration of citrate as a molar concentration, with acertain percentage of salts being sodium, hydrogen or other cations.Thus, in one embodiment, citrate is present at a concentration of fromabout 0.17 to about 0.37 Molar. Another embodiment includes citrate at aconcentration of from about 0.2 to about 0.36 Molar. Yet anotherembodiment (9% citrate) includes citrate at a concentration of about0.31 Molar.

At a citrate concentration of 9% by weight, the citrate has a stronganticoagulant effect in the catheter lock solution. At thisconcentration, however, it is believed that citrate alone would notprovide a significant antimicrobial property. The present disclosurerelates to the discovery, which has been experimentally established thata mixture of citrate and benzyl alcohol has unexpected and surprisinglyeffective antibacterial activity when used as a catheter lock solutionin accordance with the present disclosure. In a series of tests withmultiple microorganisms, solutions including citrate and benzyl alcoholdispersed or dissolved therein effectively killed all species ofbacteria tested (when undiluted), while a solution including heparin andbenzyl alcohol has little or no effect on the organisms (allowing growthof a bacterial biofilm).

In one preferred, embodiment, an inventive catheter lock solutionincludes citrate (provided, for example, in the form of trisodiumcitrate dihydrate) at a concentration of from about 5 to about 11% byweight and benzyl alcohol having a concentration of from about 0.5 toabout 2.0.

In vitro studies have indicated that the density of a lock solution isimportant in determining the length of time that the lock solutionremains in the catheter. The relative density of blood with hematocritof 32% is approximately 1.050, and increases linearly with hematocritconcentration. If a catheter lock solution with relative density higherthan this is placed into a catheter positioned vertically, the locksolution will exit from the catheter at a slow rata. Increasing theviscosity with polymeric substances such as PEG slows but does notprevent the egress of the lock solution. Therefore, in certainembodiments of the disclosure, the citrate concentration in a locksolution is selected such that the density of the lock solution issufficiently close to the density of the patient's blood that thesolution does not exit the catheter during the lock period to anunacceptable degree.

In one aspect of the disclosure, therefore, a catheter lock solutioncomprising citrate and benzyl alcohol according to any embodimentdescribed in this disclosure is provided that has a density of fromabout 1.030 to about 1.060 g/ml. In another embodiment, a lock solutioncomprising citrate and benzyl alcohol has a density of from about 1.035to about 1.060 g/ml. In still another embodiment, a lock solutioncomprising citrate and benzyl alcohol is provided having a density offrom about 1.040 to about 1.060 g/ml. In yet another embodiment, aninventive lock solution comprising citrate and benzyl alcohol has adensity of from about 1.045 to about 1.055 g/ml. It is understood thatthe density of a given patient's blood may differ from the density ofthe blood of another patient. Thus, the present disclosure alsocontemplates matching the relative density of a catheter lock solutionto within a predetermined tolerance of the relative density of wholeblood of a given patient (such as, for example, within 0.010 g/ml of therelative density of the patient's blood). Such density matching iswithin the purview of a person of ordinary skill in the art in view ofthe present description. Closely matching the densities has theadvantageous effect of aiding in the retention of the catheter locksolution within the catheter between treatments. When the relativedensities are relatively close, gravitational force does not tend tourge the catheter lock solution out of the catheter when the patient isupright. Similarly blood will not enter the catheter when the catheteris upward directed as in the femoral vein when the patient is standing(as can happen with a low-density catheter lock such as heparin).

In another aspect of the disclosure, the catheter lock solution may alsoinclude an agent to modify viscosity. The presence of a viscosifyingagent is particularly useful, for example, when the relative density ofa given catheter lock solution is not the same as the density of apatient's blood.

Therefore, in certain preferred embodiments, a lock solution is providedthat comprises citrate and benzyl alcohol according to any embodimentdescribed in this disclosure and one or more agents to adjust viscosityto help retain the lock within the catheter for a desired amount oftime. It is well known that catheters are manufactured to have a varietyof configurations and lumen diameters. For example, catheters caninclude single or double lumens. The double lumens can be fused adjacentto each other or they can be concentric. The lumens can have varyingcross-sectional areas and shapes, ranging from substantially circular tosubstantially ovoid. As discussed above, a phenomenon common to mostlock solutions is that a portion of the solution at the distal end ofthe lumen diffuses into the patient's blood stream and is replaced inthe catheter by blood. The rate of diffusion of a lock solution from alumen can be influenced not only by the density of the lock solution,but also by the cross-sectional shape and area of the particularlumen(s) and the viscosity of the lock solution. A lock solution of thepresent disclosure is preferably prepared to have a viscosity anddensity such that a substantial portion of the lock solution does notdiffuse or flow out of a catheter lumen under normal circumstanceswithin several days.

Viscosifying agents that can advantageously be selected for use inaccordance with the present disclosure include those pharmaceuticallyacceptable agents known or commonly used in treatment of animalsincluding humans. Examples include, but are not limited to, dextran,polyethylene glycol, glycerin, polygeline, and non-metabolizable sugarssuch as sorbitol and mannitol and mixtures of these compounds.Viscosifying agents that increase the viscosity of a lock solution allowa higher concentration of citrate to be used without having anunacceptable degree of egress of the lock solution from the catheter dueto high density of the lock solution.

While it is understood that optimal viscosity and density are dependent,upon the shape and size of a particular lumen, a person of ordinaryskill in the art, in view of the description herein, can readilydetermine a desired density and viscosity for a particular catheterwithout undue experimentation. It is of course understood that the needfor viscosifying agents is reduced or eliminated in a lock solutionhaving a relatively low concentration of citrate and a density closelymatched to that of blood. The antiseptic effect of the citrate, which isreduced by the reduction in the citrate concentration, is still achievedby the inclusion of benzyl alcohol in an amount whereby the citrate andbenzyl alcohol together exhibit an antiseptic effect.

An inventive lock solution according to any embodiment described in thisdisclosure can be prepared to include a variety of otherpharmaceutically acceptable agents. For example, the lock solution caninclude salts, such as, for example, sodium chloride or other sodiumsalts. The lock solution can also include a variety of otherantibacterial, antimicrobial and anticoagulant agents. Suchantibacterial and antimicrobial agents are well known to those skilledin the art and can include, without limitation, gentamicin, vancomycin,and mixtures of these agents. Additional anticoagulant agents that canbe included in an inventive catheter lock solution include, for example,heparin, urokinase, tissue plasminogen activation (tPA) and mixtures ofthese agents. When the anticoagulant includes heparin, the heparin ispreferably present at a concentration of from about 100 units/ml toabout 10,000 units/ml.

By “pharmaceutically acceptable”, it is meant that the lock solution andthe included salts and other additives which are, within the scope ofsound medical judgment, suitable for use in contact with tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, and are commensurate with the reasonablebenefit/risk ratio. It is also typically necessary that a composition besterilized to reduce the risk of infection. For example,pharmaceutically acceptable salts are well-known in the art, andexamples can be found in S. M. Berge et al. described in detail in J.Pharmaceutical Science, 66:1-19, 1977.

Compositions described herein can be prepared with simple mixing at roomtemperature.

In addition to inventive catheter lock solutions, as described above,the present disclosure also provides methods of inhibiting infections inan animal having an indwelling intravascular catheter. In one aspect,therefore, the disclosure provides a method that includes selecting apatient having an indwelling catheter defining a lumen therethrough, andinfusing an aqueous catheter lock solution into the lumen, the solutioncomprising citrate and benzyl alcohol according to any embodimentdescribed in this disclosure dispersed or dissolved therein. In apreferred manner of practicing the disclosure, the method comprisesinfusing an amount of the lock solution that is from about 80% to about120% of the internal volume of the catheter being locked.

Once a lock solution is infused into the lumen of a catheter inaccordance with the disclosure, it is preferably allowed to remain untilit is time to access that particular catheter or lumen again. It isdesirable to remove the catheter lock, before starting the dialysisprocedure or using the catheter for fluid infusion, especially if thecatheter lock solution includes heparin.

In other aspects of the disclosure, the catheter lock solutioncontaining citrate and benzyl alcohol according to any embodimentdescribed in this disclosure may be injected into catheters used foraccess to other body spaces besides veins or arteries. For example,catheters used in peritoneal dialysis access the peritoneum (the spacedefined by the peritoneal membrane and exterior to the organs in theabdomen). These catheters also have a risk of bacterial and fungalcontamination. After draining and infusing peritoneal dialysatesolutions, a lock solution including citrate and benzyl alcoholaccording to any embodiment described in this disclosure is infused intothe catheter. Other catheters with risk of infection include cathetersin the urinary bladder, the cerebral spinal fluid (around the centralnervous system) and the subcutaneous space (under the skin). The presentdisclosure contemplates introducing a catheter lock solution asdescribed herein into the lumens of these and other types of catheters.

In another aspect, the disclosure involves an infusion device forinfusing a lock solution into a lumen of a catheter. The infusion deviceincludes a syringe and a pharmaceutically acceptable lock solutioncontained within the syringe, the lock solution including citrate andbenzyl alcohol according to any embodiment described in this disclosuredispersed or dissolved therein. In a preferred embodiment, the syringecontaining the lock solution is sterilized. The syringe can beadvantageously used to infuse a catheter lock solution into a catheterthat has an injection port affixed thereto by attaching a needle to thesyringe and injecting the needle into the port. Alternatively thesyringe can be used by uncapping a catheter and attaching the syringedirectly to the catheter.

In another aspect of the disclosure, there is provided a catheter lockkit. In one preferred embodiment, a kit includes a container havingtherein a catheter lock solution, the catheter lock solution comprisingcitrate and benzyl alcohol according to any embodiment described in thisdisclosure dispersed or dissolved therein; and instructions, recorded ina medium, for infusing the solution into a lumen of an indwellingcatheter.

Various processes, methods, compositions and devices of the presentdisclosure are further discussed with reference to the followingExamples. It will be understood that these Examples are intended to beillustrative and not restrictive in nature.

Examples

As an introduction, the present inventor's laboratory was the first todiscover that concentrated citrate had antibacterial properties andfound that this property is somewhat weak at 7-10% but increasessignificantly at 23-46%. It also was the first to find that higherconcentrations of citrate had problems with egress from catheters, dueto a density much higher than that of blood. Subsequent efforts wereundertaken to augment the antibacterial function of sodium citrate withvarious compounds that have been used as preservatives and medicationswith known antibacterial effects (and which have been administeredintravenously without side effects). The objective of this undertakingwas to utilize a sodium citrate concentration with density in the rangeof human blood, but still provide strong antibacterial function. Wefirst found that photo-oxidants such as methylene blue were synergisticwith 7% sodium citrate and greatly increased the antibacterial function.We then found that parabens compounds (preservatives) were synergisticwith sodium citrate, increasing antibacterial function. Finally, wefound that the combination of sodium citrate-parabens-methylene blue(C-MB-P) was even more powerful in killing bacteria, without loss of anyof the anticoagulant effects of the citrate.

In clinical trials we demonstrated that C-MB-P offered both anantithrombotic alternative to heparin and protection against CRBSI. Inthe largest prospective randomized controlled trial to examine theutility of an alternative antithrombotic and an anti-infective locksolution, encompassing 407 patients studied for an aggregate 50,000catheter-days, we found C-MB-P to be as effective as heparin inpreserving catheter patency; none of 201 catheters followed for a meanof 150 days was lost because of patency failure (Maki D G, Ash S R,Winger R K, Lavin P; for the AZEPTIC Trial Investigators. A novelantimicrobial and antithrombotic lock solution for hemodialysiscatheters: A multi-center, controlled, randomized trial. Crit Care Med2011 Vol. 39, No. 4, 613-620.). Moreover, despite a surprisingly lowrate of CRBSI in the control group, a tribute to the quality ofinfection control practice in the study centers, patients in the C-MB-Pgroup had a 71% reduction in CRBSI with protection against all majorgroups of bacterial pathogens. The solution was at least as safe asheparin, and in the trial showed a strong trend toward reduced all-causemortality. Comparisons of composite outcome measures combining CRBSI,catheter patency and adverse outcome events, including death from anycause, also showed superiority of the C-MB-P lock solution.

With the results of this large clinical trial, an application forapproval to market C-MB-P (by then called Zuragen™) as a catheter locksolution was submitted to the FDA. While working with FDA on theclinical trial protocol and PMA application, catheter lock solutions hadbeen first considered as devices, then combination device-drugs,reviewed both by CDRH (devices) and CDER (drugs). The drug divisiondecided that because methylene blue was considered a drug, Zuragen wouldbe considered a drug. This meant that a second clinical trial would beneeded. We also found that methylene blue tended to stain productionequipment, meaning production was more expensive than desired. Also,methylene blue when given in large amounts intravenously may causeadverse reactions in some patients taking SSRI medications. Although theamounts of the catheter lock solution used to lock a catheter are toosmall to cause problems in any patient, drug interaction programs oftenalert pharmacists of potential adverse reactions between Zuragen andSSRI medications. Also, parabens have been known to cause adversehormonal effects in some patients if contacted or infused in largequantities. This was another mild marketing hurdle for Zuragen.

In a new study, we created solutions of 10% sodium citrate dihydratealso known as trisodium citrate or sodium citrate, in which the pH wasadjusted to 6.2 by addition of 0.4% citric acid. We then added 1.5%benzyl alcohol to this solution. We found that the mixture (C-BA) wentinto solution somewhat slowly, over 1-2 hours at room temperature, butthat the resulting solution was perfectly clear and stable for months atroom temperature or at refrigerator temperatures. The density of thefinal solution was 1.058 g/mL, which is close to the average density ofhuman blood with normal hematocrit (1.050-1.060 g/mL). This means thatgravitational forces should not cause the lock solution to exit centralvenous catheters regardless of the patient's position.

The antibacterial function of C-BA was tested and compared to that ofsodium citrate solution without benzyl alcohol (C). To assure that thelock solutions were sterile, we filtered samples after productionthrough 0.2 micrometer membranes. In the following description ofprocedure, method and results, lock solution identity is as follows:

Lock solution A=10% sodium citrate (C, above)

Lock solution B=10% sodium citrate with 1.5% benzyl alcohol (C-BA,above).

Procedure: “Lock Solution” (LS) A and B were prepared and, beforeconducting Minimal Inhibitory Concentration (MIC) tests of thesolutions, both of them were inoculated into Brain Heart Infusion (BHI)broth and proved to be sterile. Six bacterial strains were recoveredfrom frozen stocks in a −80° C. freezer for each test. Fresh bacteriacultures were incubated with different dilution of each LS inMueller-Hinton broth (MHB) in 96-well microtiter plates at 37° C. forovernight. Each strain was inoculated in triplicated wells and everyexperiment was repeated for at least twice. The overall results werecalculated, analyzed and interpreted.

Materials and Methods

Chemicals: LS A and B were prepared, stored at 4° C. and used for theexperiments at room temperature.

Bacterial strains, growth conditions, sterility test, and pHmeasurements: Six bacterial pathogens including three Gram-negativebacteria (Klebsiella pneumoniae ATCC 33495, Escherichia coli O157:H7 EDL933, and Pseudomonas aeruginosa ATCC 10145) and three Gram-positivebacteria (Staphylococcus aureus ATCC25923, methicillin-resistantStaphylococcus aureus ATCC43300, and Streptococcus mutans ATCC25175)were used in this study. All bacterial cultures were procured fromAmerican Type Culture Collection (ATCC), Manassas, Va. Bacterialcultures were stored as frozen glycerol (20%) stock at −80° C. A loop offrozen bacterial stock was first streaked on Brain-heart infusion (BHI)agar media and incubated for 18 h at 37° C. to obtain a pure colony.Pure single colony was grown in tryptic soy broth (TSB) for 18 h at 37°C. and 130 rpm. To enumerate bacterial cell density, 18 h grown cultureswere serially 10-fold diluted in phosphate-buffered saline (PBS, pH 7.4)and plated on BHI agar plates. Sterility of these catheter locksolutions were also tested by inoculating 100 μL into 4 mL BHI broth andincubated at 37° C.

Minimum Inhibitory Concentration (MIC): The MIC values of LS A and B forsix bacterial strains used in this study was determined usingmicro-titer plate dilution method (Andrews, 2001) after takingspectrophotometric absorbance measurements at 595 nm with micro-titerplate reader (Epoch, BioTek, Winooski, Vt.). All MIC experiments wereperformed in MHB. 100 μl different dilutions of LS (½, ¼, ⅛, 1/16, 1/32)were mixed with 100 uL of approximately 106 cells bacteria in 2×MHB.Each test was done in triplicate wells of a 96-well microtiter plate,which was further incubated at 37° C. and 70 rpm for 24 h. MHB alone andMHB with bacterial inoculum was used as negative and positive control,respectively. Two experimental replicates were performed to calculatethe average MIC value±SD.

Results

Sterility of LS A and LS B samples: After incubating at 37° C. for over24 hr, there was no turbidity in the BHI broth inoculated with LS A andLS B, suggesting they are sterile.

Minimum inhibitory concentrations (MIC): Inhibition assay performed withLS A (FIG. 2) and LS B (FIG. 3) against the six bacterial pathogensrevealed that ½ dilution of LS B inhibits the growth of all pathogenstested. Moreover, the highest concentration of LS A did notsignificantly suppress the growth of E. coli EDL933, P. aeruginosaATCC10145 and K. pneumoniae ATCC33459.

The combination of sodium citrate solution and benzyl alcohol (C-BA) hasconsiderable antibacterial potency. At 1:2 dilution, C-BA completelyeliminates growth of all six strains of bacteria tested. This means ofcourse that at full strength it would also eliminate bacterial growth.In fact for gram negative organisms (E Coli, Pseudomonas andKlebsiella), dilutions of C-BA at 1:8 completely eliminated growth, asshown in FIG. 3. By contrast the sodium citrate solution alone (C) at1:2 completely eliminated only 3 of the 6 strains of bacteria tested,and none of the gram negative organisms, as shown in FIG. 2. In view ofthis, together with the testing of benzyl alcohol alone as discussedbelow, we find that the marked antibacterial effect of C-BA is due to asynergistic antibacterial effect of sodium citrate with benzyl alcohol.

Benzyl alcohol, in the presence of high concentrations of bacteria,would be expected to decrease the bacterial concentration by 2-3 logs(100 to 1000 fold decrease). Benzyl alcohol is commonly added to heparinlock solutions as a preservative. In a previous study, our laboratorytested the antibacterial effect of heparin-benzyl alcohol and foundresults shown in FIG. 3.

In FIG. 3, the second set of bars shows the reduction of bacteriaconcentration in biofilm and in planktonic suspensions, in presence of5000 units/mL heparin with 1% benzyl alcohol. The heparin-benzyl alcoholsolution in full strength resulted in a 1-2 log reduction in bacterialnumber in a suspension of S. Aureus. Thus the full-strengthconcentration of benzyl alcohol alone did not reach inhibitoryconcentration for bacteria in a heparin solution. This is furtherevidence that the marked antibacterial effect of C-BA is due to asynergistic antibacterial effect of sodium citrate with benzyl alcohol.

Synergistic effects of sodium citrate with other preservatives such asparabens and with photo-oxidants has been shown by previous work in ourlaboratory. Our C/MB/P (Zuragen) lock solution combined sodium citratewith methylene blue and parabens. As shown in the FIG. 3, C/MB/P didreach an inhibitory concentration at full strength, in a suspension ofS. aureus. Further tests demonstrated very high MIC values for all grampositive organisms, but not very high MIC values for gram negativeorganisms, as shown in FIG. 4.

Gram positive bacteria are the infecting organisms in the majority ofcatheter related blood stream infections (CRBSI), but almost as manyinfections are caused by gram negative organisms. It is ideal to have acatheter lock solution that will kill both gram negative and grampositive organisms. C-BA provides more broad-spectrum bacterial killingthan C/MB/P, though the MIC level of C/MB/P for gram positives isconsiderably higher than that for C-BA.

In other studies, we have demonstrated that preservative compoundsincluding alcohols do not adversely affect the antithrombotic effects ofsodium citrate. With a sodium citrate concentration of 10% in C-BA, theantithrombotic effects should be considerably more effective than thecurrently used heparin solutions.

While exemplary embodiments incorporating the principles of the presentapplication have been disclosed herein, the present application is notlimited to the disclosed embodiments. Instead, this application isintended to cover any variations, uses, or adaptations of theapplication using its general principles. Further, this application isintended to cover such departures from the present disclosure as comewithin known or customary practice in the art to which this presentapplication pertains and which fall within the limits of the appendedclaims.

As will be appreciated by a person of ordinary skill in the art uponreading the information disclosed above, in one aspect, the presentdisclosure provides an aqueous antimicrobial solution comprising about 5to about 11% by weight citrate and about 0.5 to about 2.0 percent byweight benzyl alcohol dispersed or dissolved therein. In one embodiment,the concentration of citrate in the solution is at least as high as thecalcium concentration in a patient's blood. In another embodiment, theconcentration of citrate in the solution is from about 6 to about 10.5%by weight. Additional embodiments include any other embodiment disclosedherein wherein the citrate is trisodium citrate dehydrate. The presentdisclosure also contemplates all embodiments described herein whereinthe pH of the solution is from about 5 to about 7.5. The presentdisclosure also contemplates all embodiments described herein whereinthe pH of the solution is from about 6 to about 7. The presentdisclosure also contemplates all embodiments described herein whereinthe relative density of the solution is from about 1.030 to about 1.060g/ml. The present disclosure also provides embodiments in which any ofthe embodiments disclosed above further includes a viscosifying agent.The present disclosure also contemplates all embodiments describedherein wherein the viscosifying agent comprises dextran, polyethyleneglycol, glycerin, polygeline, a non-metabolizable sugar, or acombination thereof. The present disclosure also contemplates allembodiments described herein wherein the citrate has a concentration offrom about 6 to about 10.5% by weight and the concentration of benzylalcohol is from about 0.5 to about 1.7% by weight.

In another aspect, the present disclosure provides a method ofinhibiting infection in an indwelling catheter defining at least onelumen therethrough, the method comprising infusing an aqueous catheterlock solution into a lumen of the catheter, the solution comprisingabout 5 to about 11% by weight citrate and about 0.5 to about 2.0percent by weight benzyl alcohol. In one embodiment, the concentrationof citrate in the solution is at least as high as the calciumconcentration in a patient's blood. In another embodiment, theconcentration of citrate in the solution is from about 6 to about 10.5%by weight. Additional embodiments include any other embodiment disclosedherein wherein the citrate is trisodium citrate dihydrate. The presentdisclosure also contemplates all embodiments described herein whereinthe pH of the solution is from about 5 to about 7.5. The presentdisclosure also contemplates all embodiments described herein whereinthe pH of the solution is from about 6 to about 7. The presentdisclosure also contemplates all embodiments described herein whereinthe relative density of the solution is from about 1.030 to about 1.060g/ml. The present disclosure also provides embodiments in which any ofthe embodiments disclosed above further includes a viscosifying agent.The present disclosure also contemplates all embodiments describedherein wherein the viscosifying agent comprises dextran, polyethyleneglycol, glycerin, polygeline, a non-metabolizable sugar, or acombination thereof. The present disclosure also contemplates allembodiments described herein wherein the citrate has a concentration offrom about 6 to about 10.5% by weight and the concentration of benzylalcohol is from about 0.5 to about 1.7% by weight.

The terminology used herein is for the purpose of describing particularillustrative embodiments only and is not intended to be limiting. Asused herein, the singular forms “a”, “an” and “the” may be intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. The terms “comprises,” “comprising,” “including,” and“having,” are inclusive and therefore specify the presence of statedfeatures, integers, steps, operations, elements, and/or components, butdo not preclude the presence or addition of one or more other features,integers, steps, operations, elements, components, and/or groupsthereof. The method actions, processes, and operations described hereinare not to be construed as necessarily requiring their performance inthe particular order discussed or illustrated, unless specificallyidentified as an order of performance. It is also to be understood thatadditional or alternative actions or operations may be employed.

Although the terms first, second, third, etc. may be used herein todescribe various elements, components, regions, layers and/or sections,these elements, components, regions, layers and/or sections should notbe limited by these terms. These terms may be only used to distinguishone element, component, region, layer or section from another region,layer or section. Terms such as “first,” “second,” and other numericalterms when used herein do not imply a sequence or order unless clearlyindicated by the context. Thus, a first element, component, region,layer or section discussed herein could be termed a second element,component, region, layer or section without departing from the teachingsof the example embodiments.

While the invention has been illustrated and described in detail in thedrawings and foregoing description, the same is to be considered asillustrative and not restrictive in character, it being understood thatonly certain exemplary embodiments have been shown and described andthat all changes and modifications that come within the spirit of theinventions are desired to be protected.

1. An aqueous antimicrobial solution comprising about 5 to about 11% byweight citrate and about 0.5 to about 2.0 percent by weight benzylalcohol dispersed or dissolved therein.
 2. The solution of claim 1,wherein the concentration of citrate in the solution is at least as highas the calcium concentration in a patient's blood.
 3. The solution ofclaim 1, wherein the concentration of citrate in the solution is fromabout 6 to about 10.5% by weight.
 4. The solution of claim 1, whereinthe citrate is trisodium citrate dihydrate.
 5. The solution of claim 1,wherein the pH of the solution is from about 5 to about 7.5. 6.(canceled)
 7. The solution of claim 1, wherein the relative density ofthe solution is from about 1.030 to about 1.060 g/ml.
 8. The solution ofclaim 1, wherein the solution further comprises a viscosifying agent. 9.(canceled)
 10. (canceled)
 11. A catheter lock solution to preventclotting of central venous catheters and to kill bacteria contaminatingthe interior lumen of the catheters comprising: about 10% concentrationof sodium citrate dihydrate, and about 0.5 to about 1.5% benzyl alcohol.12. The solution of claim 11, in which the pH is adjusted to a range ofabout 6.0 to about 6.5 by addition of citric acid or other form of acid.13. A method to prevent clotting of central venous catheters and to killbacteria contaminating the interior lumen of the catheters using thecatheter lock solution of claim
 11. 14. A method of inhibiting infectionin an indwelling catheter defining at least one lumen therethrough, themethod comprising infusing an aqueous catheter lock solution into alumen of the catheter, the solution comprising about 5 to about 11% byweight citrate and about 0.5 to about 2.0 percent by weight benzylalcohol.
 15. The method of claim 14 wherein the catheter is anintravascular catheter or a body cavity catheter.
 16. The method ofclaim 14 wherein the lumen of the catheter has an internal volume andthe method comprises infusing an amount of the lock solution that isfrom about 80% to about 120% of the internal volume of the lumen. 17.The method according to claim 14 wherein the concentration of citrate inthe solution is at least as high as the calcium concentration in apatient's blood.
 18. (canceled)
 19. The method according to claim 14wherein the citrate is trisodium citrate dihydrate.
 20. The method ofaccording to claim 14 wherein the pH of the solution is from about 5 toabout 7.5.
 21. (canceled)
 22. The method according to claim 14 whereinthe relative density of the solution is from about 1.030 to about 1.060g/ml.
 23. The method according to claim 14 wherein the solution furthercomprises a viscosifying agent.
 24. (canceled)
 25. The method accordingto claim 14, wherein the catheter is in a patient.
 26. The methodaccording to claim 25, wherein the catheter is surgically implanted.